Human skin is composed of two compartments, namely a deep compartment, the dermis, and a superficial compartment, the epidermis.
The skin constitutes a barrier against external aggressions, especially those of chemical, mechanical or infectious type, and, there are certain number of reactions which take place therein, these being defence reactions against environmental factors (climate, ultraviolet radiation, tobacco, etc.) and/or xenobiotics, for example microorganisms. This property, referred to as the barrier function, is provided principally by the most superficial layer of the epidermis, namely the horny layer, called the stratum corneum.
It is clear that the quality of the skin barrier and of the mucous membranes is affected daily following external aggressions by irritant agents (detergents, acids, bases, oxidants, reductants, concentration solvents, gases or toxic fumes), mechanical stresses (friction, impacts, abrasion, tearing of the surface, dust projection, particle projection, shaving or hair removal) or thermal or climatic imbalances (cold, dryness).
Skin irritation is conventionally defined as a local, reversible and non-immunological, inflammatory reaction characterized by oedema and erythema, which is induced after single or repeated contact of a chemical substance with the skin.
Substances belonging to different classes of very different chemical products, such as keratinic solvents, dehydrating agents or oxidant or reductant agents, may be considered to be irritants.
Irritation of the skin is a very significant phenomenon, representing as it does, approximately, between 60% and 80% of clinical cases of non-allergic contact dermatitis. The majority of the other cases represent allergic contact dermatitis.
Irritant contact dermatitis (ICD) is a multi-factor disease, triggered as a function of both intrinsic and extrinsic factors. Age, genetic background and sex are also factors which may influence the development of this pathology.
Acute irritant contact dermatitis (ICD) is characterized principally by inflammation, whereas chronic ICD is characterized by hyperproliferation of keratinocytes and by transitory hyperkeratosis.
The biochemical events involved in skin irritation are complex and very little described.
It is known that skin irritation involves a cascade of reactions which, via the recruitment of infiltrating blood cells (neutrophils, macrophages, Langerhans cells) and the substances that they release (cytokines, lymphokines, chemokines, etc.), gives rise to the persistent irritant process which is characterized primarily in irritation of the skin.
The penetration of the skin by chemical compounds is a major parameter in the establishment of the physiopathology of ICD. The latter is associated with the degree of permeability of the skin (which is linked to its physiological condition) and with physicochemical properties of the compounds whose ingress it is thought to restrict (molecular weight, polarity, ionization state) and with the nature of the environment (excipient, vehicle) via which these substances are brought into contact with the skin.
This inevitable step corresponds, on the basis of the external medium or the vehicle, to the release of the molecule which is to diffuse, and therefore to its provision to the body.
In the case of contact between an irritant and the skin, the keratinocytes are the first cells to be activated by the chemical product. The majority of studies into ICD have therefore focused on this type of cell, and numerous data have since become known with regard to their involvement in the physiopathology of ICD. The keratinocytes play an important part in initializing the inflammatory skin reaction, through the release of numerous mediators and cytokines, which underlie a whole cascade of inflammation, ending in the clinical signs of ICD. Among these, IL-1α and derivatives of arachidonic acid possess particular importance in the development of inflammation. Whereas a major part is played by oxidative stress, the part of TNF-α appears to be more controversial.
The release of IL-1α induces, via the activation of the transcription factor NF-kB, the transcription of genes involved in inflammation, such as cytokines IL-1α, IL-6, GM-CSF, TNF-α, chemokines including IL-8, MCP-1, MIP-1α and eotaxin, and also the expression of adhesion molecules such as E-selectin, ICAM-I and VCAM-I (Gordon J R, Nature 1990: 346 (6281): 274-276).
The signalling cascade generated from the activation of the keratinocytes begins from the release of prestored key mediators. In fact, resting keratinocytes contain a large amount of preformed and biologically active IL-1α (Marks F et al., Toxicol Lett 96: 111-118, 1998), and also of arachidonic acid (Murphy J E et al., J Invest Dermatol 114: 602-608, 2000).
Because these two compounds are produced constitutively by keratinocytes, and remain stored in the cell, the epidermis may be considered to be a major reservoir of highly inflammatory mediators. Impairment of the keratinocytes owing to the corrosive effect of a chemical compound, a burn, or by UV exposure automatically induces the release of IL-1α and of arachidonic acid, which become the first defence events of the body.
Accordingly, IL-1α and arachidonic acid might be considered to be the key mediators in triggering irritation in response to a chemical stress (Murphy J E et al., J Invest Dermatol, 114: 602-608, 2000).
Among all of the mediators of information, apart from IL-1 and arachidonic acid, only TNF-α is able to activate a sufficient number of mechanisms to generate skin inflammation independently. This major cytokine of skin inflammation is already prestored in the dermal mastocytes (Larrick J W et al., J Leukoc Biol, 45: 429-433, 1989), but it is also produced by the keratinocytes and the Langerhans cells after stimulation (Groves R W, et al., J Invest Dermatol, 98: 384-387, 1992). One of the mechanisms via which TNF-α exerts the most influence on the inflammatory reaction is the induction of adhesion molecules in synergy with IL-1. Adhesion molecules play an essential part in the circulation and penetration of leukocytes (especially neutrophils) from the peripheral blood vessels to the dermis and epidermis (Holliday M R et al., Am J Contact Dermat, 8: 158-164, 1997).
Numerous chemical products may induce skin irritation; however, they differ in their capacity to generate pro-inflammatory cytokines, and skin inflammation is not systematically dependent on the production of TNF-α.
It is important to note as well that the production of IL-12 and of IL-18 by the activated macrophages at the site of the inflammation plays an important part as a local amplification loop. This is because these cytokines stimulate the production of IFN-α by neighbouring T lymphocytes, which is, in turn, a powerful coactivation factor for the macrophages and the keratinocytes.
Finally, with regard to exogenous stress, it is known that, under particular circumstances, topical compounds may result in the appearance of skin reactions, when they are used in cosmetic or dermatological compositions—for other effects, of course.
Accordingly, cosmetic compositions are used that contain, for example, active keratolytic and/or desquamating agents for combating ageing, and especially active exfoliants and/or active agents which promote cell renewal, such as α-hydroxy acids (especially lactic, glycolic or citric acids), β-hydroxy acids (especially salicylic or n-octanoyl-5-salicylic acids), and retinoids (especially all-trans or 13-cis retinoic acid and retinol). Unfortunately, if these active agents are used in excessive quantities, they can provoke skin irritation. Generally speaking, the skin disorders referred to above are most frequent in the most exposed areas of the body, namely the hands, feet, face, and scalp.
They may occur in particular in areas which are subject to certain operations of daily, or frequently repeated, hygiene, such as shaving, hair removal, cleaning with toilet products or household products, application of adhesives (plasters, patches, attachment of prostheses), or in the case of actions involved in sport, in work or simply associated with lifestyle and with the use of clothing, tools or equipment that gives rise to localized friction. They may also be amplified by psychological stress.
Consequently, it would appear to be valuable to have an effective active agent available for preventing and/or treating and/or reducing these disorders, and more particularly the skin irritation.